CMV Infection - Medical Information PDF

2.3.5. Cytomegalovirus infection (CMV) Cytomegalovirus (CMV) or human herpes virus 5, belongs to the beta (β) Herpesvirus subfamily, infecting monocytes, neutrophils, renal epithelial cells, salivary glands and vascular endothelial cells. At the tissue level it produces a typical cytopathic...

2.3.5. Cytomegalovirus infection (CMV) Cytomegalovirus (CMV) or human herpes virus 5, belongs to the beta (β) Herpesvirus subfamily, infecting monocytes, neutrophils, renal epithelial cells, salivary glands and vascular endothelial cells. At the tissue level it produces a typical cytopathic effect - cells "with an Owl's-eye" appearance. In immunocompetent individuals, the clinical picture of the primary CMV infection is similar to that of infectious mononucleosis (heterophile-negative infectious mononucleosis) or may be asymptomatic, while reactivation of the latent infection in immunocompromised patients may severely affect the liver, lungs, intestines, brain or nerves, and can as well cause an eye infection. Epidemiology. CMV infection is ubiquitous. Over 50% of adults in industrialized countries have anti-CMV IgG antibodies, a percentage that is close to 100% in underdeveloped regions, indicating that they have gone through previous infections. Primary infection is often acquired in childhood, adolescence or as a young adult, but reinfections are possible. The source of infection is the infected individual, with clinically manifest or inapparent forms of infection, who can excrete the virus for months (even 18 months) after the first infection even if he is asymptomatic. CMV is excreted in saliva and urine, can be sexually transmitted, by whole blood transfusion or leukocyte-based blood derivatives (blood leukocytosis reduces the risk of transmission), by bone marrow or solid organ transplantation, respectively from mother to fetus (most often transplacental, possibly during intrapartum or through breastfeeding). A particular category is represented by women of reproductive age, who can acquire CMV infection during pregnancy, with the risk of maternal-fetal transmission, the main source being another child in the family, who in turn can acquire CMV infection through saliva, from contacts in day care centers, kindergartens, etc. The immune response is both humoral, through the synthesis of IgM- antibodies, later IgG, as well as cellular, involving T lymphocytes. Pathogenesis Following primary infection, CMV can be detected in circulating leukocytes (monocytes, PMN), salivary gland cells, renal epthelial cells and the vascular endothelium. Histopathological examination highlights the cytopathic effect - the occurrence of giant cells, with large eosinophilic intranuclear inclusions, with peripheral halo, the pathognomonic "owl's eyes" appearance. Immunodepression, especially affecting T lymphocytes (post-transplant, haematological neoplasms, HIV infection), is a risk factor for reactivating latent infections. Congenital CMV infection is most often due to the maternal acquisition of the primary infection during pregnancy. Rarely, it may be due to reactivation of latent maternal CMV infection during pregnancy, or reinfection with another viral strain. Clinical picture Primary CMV infection in immunocompetent patients may progress oligo- / asymptomatically or may produce a clinical mononucleosis-like syndrome (infectious mononucleosis without heterophilic antibodies). After a prolonged incubation (20-60 days), the clinical picture can be represented only by a prolonged febrile syndrome - 2-3 weeks, sometimes may be associated with lymphadenopathy, hepatosplenomegaly, pharyngitis (rarely exudative), scarlatiniform, pustular, plaque-like, or maculopapular rash, associated with the administration of aminopenicillin. In most cases the infection is self-limited, with a post-infective fatigue syndrome. Complications include meningoencephalitis, polyradiculoneuritis (Guillain-Barre syndrome), myelitis, interstitial pneumonia, hemolytic anemia, pancytopenia, macrophage activation syndrome, splenic rupture, myocarditis, and pericarditis. CMV infection in immunocompromised people usually takes severe forms. It is the most common consequence of reactivation of latent infection under immunosuppression, but may also be caused due to the acquisition of a new CMV infection in an immunocompromised host - e.g. CMV transmission through transplanted organ (liver, heart, kidneys, lung). Clinical manifestations may be related in this case to the type of transplant – e.g. hepatitis after liver transplantation, pneumonia after lung transplantation, but may also include rejection of organ transplantation (pulmonary, cardiac) or graft-versus-host reaction (e.g. after bone marrow transplantation). In HIV-positive patients, CMV infection is reactivated when the CD4+ T lymphocyte count is > 100 / mm3. The most common manifestation is CMV retinitis (examination of the fundus - characteristic appearance of "cheese and ketchup"), which can lead to blindness, but colitis, esophagitis, interstitial pneumonia, encephalitis, myelitis, polyradiculoneuritis or disseminated disease can also appear. Extrahepatic CMV disease is also an AIDS-defining disease. Congenital CMV infection can lead to miscarriage, premature birth, delayed fetal growth (intrauterine growth restriction). Clinical manifestations include microcephaly, intracerebral calcifications, chorioretinitis, blindness, deafness, petechiae, hepatosplenomegaly, jaundice, and laboratory changes - hemolytic anemia, thrombocytopenia, elevated transaminases level and hyperbilirubinemia. Mortality among newborns with major malformations is 20- 30%, and 30-40% of symptomatic survivors at birth will manifest a neuropsychomotor developmental delay and damage to the sensory organs (blindness, deafness). Over 80% of congenital CMV infections are asymptomatic at birth - 5-25% of them will develop neurological / sensory sequelae in the future. Laboratory diagnosis Serological tests. Detection of serum IgM anti-CMV antibodies (Ac) in the absence of IgG type indicates recent infection. The presence of serum anti-CMV IgG antibodies and the absence of IgM type indicates that the infection is chronic, older, without having the possibility to confirm whether it is active or not. If the patient is positive for both anti-CMV IgM and IgG antibodies, this may be a clear evidence for recent primary infection, a reinfection or a reactivation of a chronic infection. In this case, if the patient is pregnant, it is important to determine how recent the infection is. In fact, the determination of anti-CMV IgM and IgG antibodies as a screening is recommended in the first trimester of pregnancy (TORCH screen). The avidity test of anti-CMV IgG antibodies against viral antigens can specify how recent the infection is - if the avidity is low, below 30%, the infection has occurred in the last 3 months, if the avidity is elevated, the infection is older. In case of suspicion of a congenital CMV infection, in addition to serological tests, amniocentesis with detection of CMV-DNA (by PCR) in amniotic fluid may be required. Fetal ultrasound (sonogram) can detect birth defects (abnormalities). In the newborn, early diagnosis of congenital CMV infection is made by detecting CMV- DNA in samples including saliva or urine in the first 15 days after birth. In immunocompromised patients, the presence of serum anti-CMV IgG antibodies only indicates the existence of a chronic infection, without being able to confirm reactivation. CMV-DNA can be detected by PCR in the blood (viral load), but also - depending on the site of the infection - in urine, antigen test of CSF, vitreous, confirming that it is an active infection. The pp65 antigenemia also confirms the reactivation of the infection, but the sensitivity is lower. CMV isolation in cell cultures is rarely used, possibly useful when testing for susceptibility to antivirals. Histopathological examination of biopsied tissues may reveal characteristic changes – cells resembling an "owl's eye" appearance. Treatment Primary infection in immunocompetent patients does not require etiological treatment, but only supportive therapy. In immunocompromised patients, the etiological treatment includes ganciclovir 2x5 mg / kg / day given as an intravenous infusion or oral ganciclovir at a dose of 900 mg twice a day. Because the side effects of these antivirals include pancytopenia, foscarnet or cidofovir is a therapeutic alternative in post-bone marrow transplant patients as well as those infected with a viral strain resistant to ganciclovir, but not without adverse reactions (e.g. nephrotoxicity). In case of ocular damage, intravitreal ganciclovir inhection can be administered. The etiological treatment inhibits viral replication and can control the progression of the disease, but does not eradicate the chronic infection, the patient remaining susceptible to a reactivation during immunosuppression. The etiological treatment is not recommended during pregnancy, valganciclovir or ganciclovir being recommended for the postpartum treatment of newborns with congenital CMV infection. Prophylaxis To date, no effective CMV vaccine has been obtained. General prophylaxis measures should be provided for immunocompromised patients or pregnant women - rigorous hygiene, avoidance of contact with saliva, blood, urine, protected sexual intercourse. In case of blood transfusions, or a transplant, the donor must be CMV-negative, an alternative being leukocyte blood transfusion. In case of transplantation, it is ideal for the donor to be CMV-negative. If the donor was CMV-positive and the transplant recipient was CMV-negative, primary prophylaxis includes 3-6 months of valganciclovir. In immunocompromised patients (transplanted or HIV-positive patients with CD4+ T lymphocyte value